The distribution and elimination of [14C]PII, the radioisotopically-labeled equivalent of the mixture of porphyrins known as Photofrin II used in the photodynamic treatment of solid tumors, were determined in tumor-free and SMT-F tumor-bearing DBA/2 Ha-DD mice. Following i.p. injection, drug was absorbed from the peritoneum with a half-life of about 1 h; elimination from plasma was rapid, declining about 1.4 logs in concentration over 48 h following i.v. administration. However, some [14C]-activity was still detectable after 75 days. Normal tissues take up the drug within about 7.5 h after administration, with peak concentrations distributed as follows: liver, adrenal gland, urinary bladder greater than pancreas, kidney, spleen greater than stomach, bone, lung, heart greater than muscle much greater than brain. Only skeletal muscle, brain, and skin located contralaterally to subcutaneously implanted SMT-F tumors had peak [14C]-activities lower than tumor tissue; skin overlying SMT-F tumors showed concentrations not significantly different (P greater than 0.3) from tumor. After 75 days all tissues examined retained some fraction of [14C]-activity, ranging from 16% for kidney to 61% for spleen, of the initial peak tissue levels. The primary route of elimination of Photofrin II was through the bile-gut pathway, with greater than 59% of the administered [14C]-activity recovered in the feces, and only about 6% in the urine, over 192 h. HPLC analyses of fecal extracts showed that mostly monomeric and other low molecular weight porphyrin components of Photofrin II were eliminated. The higher molecular weight oligomeric fractions of Photofrin II were retained in liver and spleen up to 14 days after injection.

Abstract— Carbon‐14‐labeled hematoporphyrin ([14C]HP) was synthesized by two methods, (i) Using an in vitro avian whole‐blood system, [14C]protoheme was obtained biosynthetically by incorporating [4C]aminolevulinic acid into the porphyrin ring structure. Subsequently, the [14C]protoheme was converted to [4C]HP by standard procedures, (ii) By adopting several well‐characterized chemical reactions, deuteroporphyrin was treated with [14C]acetyl chloride, giving [14C]diacetyl deuteroporphy‐rin which was readily reduced and hydrolyzed to [14C]HP (with thecarbon–14 label on the hydroxyethyl side‐chains). These two methods are simple and afford good yields of [14C]HP with moderate to high specific activities. The [14C]HP was then treated with acetic acid/sulfuric acid followed by sodium hydroxide to give [14C]HPD. Upon gel‐ and ultra‐filtration, the [14C]HPD was enriched in the so‐called tumor‐localizing fraction of HPD, giving [14C]PII with specific activities of 0.4 Ci/mol (biosynthesis) and 10 Ci/mol (chemical synthesis). These [14C]PII preparations were equivalent with respect to chromatographic and spectrophotometric characteristics, as well as tumoricidal photodynamic activity in the DBA/2 Ha‐DD mouse: SMT‐F tumor system, to the unlabeled commercial product Photofrin™ II. The distribution of [14C]PII in mouse tissues was in close agreement to that previously reported, after adjustment for dose, for [14C]HPD biosynthetically labeled in vivo (Gomer and Dougherty, 1979), as well as for Photofrin™ II, where tissue levels were determined spectrophotometrically after extraction (Dougherty and Mang, unpublished).

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In continuation of the effort to delineate the structure of Photofrin, a chromatographically well separated component of the tumor-localizing fraction was isolated and purified using a combination of gel filtration chromatography and semi-preparative high-performance liquid chromatography. This component, the least hydrophobic of the tumor-localizing fraction, was deemed to be dihematoporphyrin ether, based on mass spectrometric analysis and its behavior toward base hydrolysis and lithium aluminum hydride reduction. Although less potent than Photofrin, the purified component was an active photosensitizer.

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